Abstract：
:Dynemicin A (1), a member of the enediyne family of natural products, binds to double-stranded DNA (K(B) approximately 10(4) M(-1)) and in the presence of millimolar concentrations of a reducing cofactor such as NADPH or GSH reacts to cleave DNA. In this work, we show that the two flavin-based enzymes ferredoxin-NADP+ reductase and xanthine oxidase catalyze the reductive activation of 1 by NADPH and NADH, respectively. The enzyme-catalyzed reductive activation of 1 leads to more rapid and efficient cleavage of DNA, even with 10-20-fold lower concentrations of the stoichiometric reductant. Significantly, the enzymatic systems are also found to activate the tight-binding (K(B) > or = 10(6) M(-1)) synthetic dynemicin analogs 3 and 5 toward DNA cleavage. These same analogs do not undergo reductive activation with NADPH or NADH alone, where evidence has been obtained to support the proposal that the DNA-bound drugs are protected from reductive activation. The new enzymatic activation processes described may have important implications for chemistry occurring with 1 and synthetic analogs in vivo, as well as for the future development of dynemicin-based anticancer agents.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Myers AG,Kort ME,Cohen SB,Tom NJdoi
10.1021/bi962976nsubject
Has Abstractpub_date
1997-04-01 00:00:00pages
3903-8issue
13eissn
0006-2960issn
1520-4995pii
bi962976njournal_volume
36pub_type
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